Gene delivery is the transfer of genetic material into recipient cells to alter some functions. As the spontaneous entry of naked nucleic acids into cells is unfortunately very ineffective, gene delivery vectors have made their breakthrough in basic and medical research [1]. Viral vectors-based gene delivery can achieve higher transduction efficiency and long-lasting effects, but they are associated with some shortcomings [2]. Non-viral gene-delivery agents, i.e., cationic lipids and polymers, self-assemble with polyanionic nucleic acids to give rise to nano- and micro-particles called lipoplexes and polyplexes, respectively, that are taken up by cells to elicit their function, but do not possess the required efficacy yet [3]. In fact, although safer than recombinant viruses, non-viral vectors currently available do unfortunately suffer from low transfection efficiency and/or remarkable cytotoxic effects [4]. The grail of gene delivery is the design of vectors and other means as effective and non-cytotoxic as possible, i.e., that are capable of safe permeation of the biological barriers and targeted delivery to intended therapeutic sites at sub-cellular precision level. In this context, collaborations between medicine, engineering, chemistry and biology are therefore essential to develop new gene delivery systems. This talk will chronicle the road towards the development of more and more effective gene delivery vectors. To elicit the desired outcome, major strides forward have been made in the development of stimuli-responsive gene delivery vectors that actively respond to changes in the (micro)environment (e.g., enzymes, pH) by altering their properties and behaviour. In this regard, a new class of very promising redox-responsive gene delivery vectors will be presented, and some insight into their mechanism of action depicted [5-9]. Key issues of gene delivery, such as why and how to shape nanometric and micrometric gene delivery complexes [10], which is the effect of the interplay between gene delivery complexes and biological fluids [11, 12], how to harness gene delivery vectors with cell-targeting properties [13] and antimicrobial activity [14, 15] will be dealt with. In order to speed up the optimisation process, there really is an urgent need to develop new tools and technologies for the unbiased, straightforward, and quantitative assessment of transfection efficiency and cytotoxicity. A promising approach facing such biologically relevant issues relies on the design of miniaturized and easy-to-use devices. Lab-on-chip (LoC) platforms to perform transfection assays for unbiased, high-throughput selection of more and more effective gene delivery vectors will be presented as well [16, 17]. References: [1] D. Pezzoli, G. Candiani, Journal of Nanoparticle Research 15 (2013). [2] W. Wang, W. Li, N. Ma, G. Steinhoff, Current Pharmaceutical Biotechnology 14 (2013) 46-60. [3] D.W. Pack, A.S. Hoffman, S. Pun, P.S. Stayton, Nat Rev Drug Discov 4 (2005) 581-593. [4] M.A. Mintzer, E.E. Simanek, Chemical Reviews 109 (2009) 259-302. [5] G. Candiani, M. Frigerio, F. Viani, C. Verpelli, C. Sala, L. Chiamenti, N. Zaffaroni, M. Folini, M. Sani, W. Panzeri, M. Zanda, ChemMedChem 2 (2007) 292-296. [6] G. Candiani, D. Pezzoli, M. Cabras, S. Ristori, C. Pellegrini, A. Kajaste-Rudnitski, E. Vicenzi, C. Sala, M. Zanda, The Journal of Gene Medicine 10 (2008) 637-645. [7] G. Candiani, D. Pezzoli, L. Ciani, R. Chiesa, S. Ristori, PLoS ONE 5 (2010). [8] L. Ciani, G. Candiani, A. Frati, S. Ristori, Biophysical Chemistry 151 (2010) 81-85. [9] D. Pezzoli, A. Kajaste-Rudnitski, R. Chiesa, G. Candiani, Lipid-Based Nanoparticles as Nonviral Gene Delivery Vectors, Nanomaterial Interfaces in Biology, 2013, pp. 269-279. [10] D. Pezzoli, E. Giupponi, D. Mantovani, G. Candiani, Scientific Reports 7 (2017). [11] D. Pezzoli, M. Zanda, R. Chiesa, G. Candiani, Journal of Controlled Release 165 (2013) 44-53. [12] D. Maiolo, J. Colombo, J. Beretta, C. Malloggi, G. Candiani, F. Baldelli Bombelli, Colloids and Surfaces B: Biointerfaces 168 (2018) 60-67. [13] D. Pezzoli, P. Tarsini, L. Melone, G. Candiani, Journal of Drug Delivery Science and Technology 37 (2017) 115-122. [14] A. Ghilardi, D. Pezzoli, M.C. Bellucci, C. Malloggi, A. Negri, A. Sganappa, G. Tedeschi, G. Candiani, A. Volonterio, Bioconjugate Chemistry 24 (2013) 1928-1936. [15] N. Bono, C. Pennetta, A. Sganappa, E. Giupponi, F. Sansone, A. Volonterio, G. Candiani, International Journal of Pharmaceutics 549 (2018) 436-445. [16] P. Occhetta, C. Malloggi, A. Gazaneo, A. Redaelli, G. Candiani, M. Rasponi, RSC Advances 5 (2015) 5087-5095. [17] E. Giupponi, R. Visone, P. Occhetta, F. Colombo, M. Rasponi, G. Candiani, Biotechnology and Bioengineering 115 (2018) 775-784.

Converging approaches to non-viral gene delivery

Gabriele Candiani
2019

Abstract

Gene delivery is the transfer of genetic material into recipient cells to alter some functions. As the spontaneous entry of naked nucleic acids into cells is unfortunately very ineffective, gene delivery vectors have made their breakthrough in basic and medical research [1]. Viral vectors-based gene delivery can achieve higher transduction efficiency and long-lasting effects, but they are associated with some shortcomings [2]. Non-viral gene-delivery agents, i.e., cationic lipids and polymers, self-assemble with polyanionic nucleic acids to give rise to nano- and micro-particles called lipoplexes and polyplexes, respectively, that are taken up by cells to elicit their function, but do not possess the required efficacy yet [3]. In fact, although safer than recombinant viruses, non-viral vectors currently available do unfortunately suffer from low transfection efficiency and/or remarkable cytotoxic effects [4]. The grail of gene delivery is the design of vectors and other means as effective and non-cytotoxic as possible, i.e., that are capable of safe permeation of the biological barriers and targeted delivery to intended therapeutic sites at sub-cellular precision level. In this context, collaborations between medicine, engineering, chemistry and biology are therefore essential to develop new gene delivery systems. This talk will chronicle the road towards the development of more and more effective gene delivery vectors. To elicit the desired outcome, major strides forward have been made in the development of stimuli-responsive gene delivery vectors that actively respond to changes in the (micro)environment (e.g., enzymes, pH) by altering their properties and behaviour. In this regard, a new class of very promising redox-responsive gene delivery vectors will be presented, and some insight into their mechanism of action depicted [5-9]. Key issues of gene delivery, such as why and how to shape nanometric and micrometric gene delivery complexes [10], which is the effect of the interplay between gene delivery complexes and biological fluids [11, 12], how to harness gene delivery vectors with cell-targeting properties [13] and antimicrobial activity [14, 15] will be dealt with. In order to speed up the optimisation process, there really is an urgent need to develop new tools and technologies for the unbiased, straightforward, and quantitative assessment of transfection efficiency and cytotoxicity. A promising approach facing such biologically relevant issues relies on the design of miniaturized and easy-to-use devices. Lab-on-chip (LoC) platforms to perform transfection assays for unbiased, high-throughput selection of more and more effective gene delivery vectors will be presented as well [16, 17]. References: [1] D. Pezzoli, G. Candiani, Journal of Nanoparticle Research 15 (2013). [2] W. Wang, W. Li, N. Ma, G. Steinhoff, Current Pharmaceutical Biotechnology 14 (2013) 46-60. [3] D.W. Pack, A.S. Hoffman, S. Pun, P.S. Stayton, Nat Rev Drug Discov 4 (2005) 581-593. [4] M.A. Mintzer, E.E. Simanek, Chemical Reviews 109 (2009) 259-302. [5] G. Candiani, M. Frigerio, F. Viani, C. Verpelli, C. Sala, L. Chiamenti, N. Zaffaroni, M. Folini, M. Sani, W. Panzeri, M. Zanda, ChemMedChem 2 (2007) 292-296. [6] G. Candiani, D. Pezzoli, M. Cabras, S. Ristori, C. Pellegrini, A. Kajaste-Rudnitski, E. Vicenzi, C. Sala, M. Zanda, The Journal of Gene Medicine 10 (2008) 637-645. [7] G. Candiani, D. Pezzoli, L. Ciani, R. Chiesa, S. Ristori, PLoS ONE 5 (2010). [8] L. Ciani, G. Candiani, A. Frati, S. Ristori, Biophysical Chemistry 151 (2010) 81-85. [9] D. Pezzoli, A. Kajaste-Rudnitski, R. Chiesa, G. Candiani, Lipid-Based Nanoparticles as Nonviral Gene Delivery Vectors, Nanomaterial Interfaces in Biology, 2013, pp. 269-279. [10] D. Pezzoli, E. Giupponi, D. Mantovani, G. Candiani, Scientific Reports 7 (2017). [11] D. Pezzoli, M. Zanda, R. Chiesa, G. Candiani, Journal of Controlled Release 165 (2013) 44-53. [12] D. Maiolo, J. Colombo, J. Beretta, C. Malloggi, G. Candiani, F. Baldelli Bombelli, Colloids and Surfaces B: Biointerfaces 168 (2018) 60-67. [13] D. Pezzoli, P. Tarsini, L. Melone, G. Candiani, Journal of Drug Delivery Science and Technology 37 (2017) 115-122. [14] A. Ghilardi, D. Pezzoli, M.C. Bellucci, C. Malloggi, A. Negri, A. Sganappa, G. Tedeschi, G. Candiani, A. Volonterio, Bioconjugate Chemistry 24 (2013) 1928-1936. [15] N. Bono, C. Pennetta, A. Sganappa, E. Giupponi, F. Sansone, A. Volonterio, G. Candiani, International Journal of Pharmaceutics 549 (2018) 436-445. [16] P. Occhetta, C. Malloggi, A. Gazaneo, A. Redaelli, G. Candiani, M. Rasponi, RSC Advances 5 (2015) 5087-5095. [17] E. Giupponi, R. Visone, P. Occhetta, F. Colombo, M. Rasponi, G. Candiani, Biotechnology and Bioengineering 115 (2018) 775-784.
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